Interleukin-6 stimulates gene expression of extracellular matrix components in bovine mesangial cells in culture

The effect of interleukin-6 (IL-6) on gene expression of extracellular matrix components in bovine mesangial cells in culture has been investigated. IL-6 (100 U/ml) time dependently increased the steady state expression of mRNAs coding for α1 collagen III and fibronectin, both transcripts being 1.5- and 2.5-fold higher than basal level at 24 and 48 h, respectively. In contrast, IL-6 stimulated laminin mRNA expression only after 48 h incubation (2.5-fold upon basal level). These results suggest that IL-6 could favour glomerular matrix accumulation thus contributing to the development of glomerulosclerosis

The Italian document: decisions for intensive care when there is an imbalance between care needs and resources during the COVID-19 pandemic

Background: In early 2020, the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) published clinical ethics recommendations for the allocation of intensive care during COVID-19 pandemic emergency. Later the Italian National Institute of Health (ISS) invited SIAARTI and the Italian Society of Legal and Insurance Medicine to prepare a draft document for the definition of triage criteria for intensive care during the emergency, to be implemented in case of complete saturation of care resources. Methods: Following formal methods, including two Delphi rounds, a multidisciplinary group with expertise in intensive care, legal medicine and law developed 12 statements addressing: (1) principles and responsibilities; (2) triage; (3) previously expressed wishes; (4) reassessment and shifting to palliative care; (5) collegiality and transparency of decisions. The draft of the statements, with their explanatory comments, underwent a public consultation opened to Italian scientific or technical-professional societies and other stakeholders (i.e., associations of citizens, patients and caregivers; religious communities; industry; public institutions; universities and research institutes). Individual healthcare providers, lay people, or other associations could address their comments by e-mail. Results: Eight stakeholders (including scientific societies, ethics organizations, and a religious community), and 8 individuals (including medical experts, ethicists and an association) participated to the public consultation. The stakeholders’ agreement with statements was on average very high (ranging from 4.1 to 4.9, on a scale from 1—full disagreement to 5—full agreement). The 4 statements concerning triage stated that in case of saturation of care resources, the intensive care triage had to be oriented to ensuring life-sustaining treatments to as many patients as possible who could benefit from them. The decision should follow full assessment of each patient, taking into account comorbidities, previous functional status and frailty, current clinical condition, likely impact of intensive treatment, and the patient's wishes. Age should be considered as part of the global assessment of the patient. Conclusions: Lacking national guidelines, the document is the reference standard for healthcare professionals in case of imbalance between care needs and available resources during a COVID-19 pandemic in Italy, and a point of reference for the medico-legal assessment in cases of dispute

“Self stabbing sucide”: 116 casi occorsi nella città di Milano dal 1993 al 2016

Introduzione Mentre molti omicidi nel Mondo sono compiuti con armi da taglio, i suicidi realizzati con siffatta modalit\ue0 lesiva sono rari accadimenti, comprovati nello 0,5-0,7% di tutti i casi di autosoppressione; in genere, sui corpi si osserva una sola ferita mortale, per quanto possano esserne eccezionalmente osservate anche molte, che sollevano la necessit\ue0 di stabilire se trattasi di modalit\ue0 realmente suicida piuttosto che omicida. In questi casi, ulteriori informazioni per configurare l\u2019esatta natura dell\u2019accadimento, sono desumibili dall\u2019anamnesi della vittima, dai dati circostanziali e di sopralluogo, nonch\ue9 dalle caratteristiche delle lesioni e dalla loro localizzazione. In questo studio, presentiamo l\u2019analisi dei casi di suicidio con armi da taglio, occorsi a Milano in 24 anni. Materiali e metodi Sono stati analizzati retrospettivamente 23417 verbali di autopsia redatti tra il 1993 e il 2016 presso la Sezione di medicina legale dell\u2019Universit\ue0 degli Studi di Milano estrapolando da 4022 suicidi totali, solo quelli realizzati con armi da taglio. Su questi casi, abbiamo approfondito lo studio delle caratteristiche delle vittime, della distribuzione e del numero delle lesioni autoinferte e delle caratteristiche dell\u2019arma feritrice. Risultati Abbiamo desunto 116 casi di suicidio con armi da taglio di cui: 103 realizzati con modalit\ue0 semplice e 13 con modalit\ue0 complessa, che hanno visto maggiormente coinvolti maschi italiani di et\ue0 compresa tra 41-e 50 anni, affetti da patologie psichiatriche, che si sono uccisi nella propria abitazione utilizzando, prevalentemente, coltelli da cucina. Le lesioni sono risultate monodistrettuali e localizzate agli arti superiori o al torace. In tutti i casi osservati, la morte, per la presenza di lesioni \u201cda assaggio\u201d a profondit\ue0 variabile, mancanza di segni di lotta, sangue limitato all\u2019area circostante il corpo e per la direzionalit\ue0 delle lesioni, da destra a sinistra, con il gomito piegato a 90 gradi verso il corpo, \ue8 stata attribuita, anche nel caso dei suicidi complessi, a shock emorragico da azione suicida. Conclusioni Gli inusuali suicidi compiuti con armi da taglio richiedono un approccio forense completo basato su un approfondito esame della scena del crimine durante il sopralluogo giudiziario, un\u2019accurata raccolta dei dati anamnestico-circostanziali e degli esiti autoptici i quali, unitamente alle indagini tossicologiche, possono rappresentare strumenti fondamentali per esprimersi motivatamente su un giudizio di accadimento omicida piuttosto che suicida

Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection

The capacity of renin-angiotensin system (RAS) inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is started. A multimodal intervention is required to afford renoprotection in overt diabetic nephropathy. Here we assessed the effects of maximal RAS inhibition by angiotensin-converting enzyme (ACE) inhibitor plus angiotensin II type 1 receptor blocker (ARB) in combination with statin in rats with overt diabetic nephropathy. Uninephrectomized rats made diabetic by streptozotocin were orally treated from 4 (when proteinuria and renal lesions had developed) to 8 mo with vehicle, lisinopril plus candesartan, lisinopril plus candesartan plus rosuvastatin, or rosuvastatin alone. Systolic blood pressure increased in diabetic rats and was significantly lowered by combined therapies. Dual RAS blockade significantly reduced proteinuria compared with vehicle. Addition of statin further lowered proteinuria to control levels. Glomerulosclerosis was ameliorated by RAS inhibitors or statin, and regression was achieved by the addition of statin. Loss of podocytes of diabetic rats was limited by ACE inhibitor plus ARB while normalized by the three drugs. Defective nephrin expression of diabetes was increased by dual RAS blockade or statin and restored by the triple therapy. Tubular damage, interstitial inflammation, and expression of the fibrotic markers transforming growth factor (TGF)-beta 1 and phosphorylated Smad 2/3 in tubuli were significantly reduced by the triple regimen. These data suggest a strategy to target proteinuria to try to achieve regression of renal disease in diabetic patients who do not fully benefit from RAS inhibition alone

Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase

Chemokines are important players in the migration of leukocytes to sites of injury and are also involved in angiogenesis, development and wound healing. In this study, we performed microarray analyses to identify chemokines that play a role during the inflammatory and repair phase after renal ischemia/reperfusion (I/R) injury and investigated the temporal relationship between chemokine expression, leukocyte accumulation and renal damage/repair. C57Bl/6 mice were subjected to unilateral ischemia for 45 min and sacrificed 3 h, 1 day and 7 days after reperfusion. From ischemic and contralateral kidney, RNA was isolated and hybridized to a microarray. Microarray results were validated with quantitative real-time reverse transcription–PCR (QRT–PCR) on RNA from an independent experiment. (Immuno)histochemical analyses were performed to determine renal damage/repair and influx of leukocytes. Twenty out of 114 genes were up-regulated at one or more reperfusion periods. All these genes were up-regulated 7 days after I/R. Up-regulated genes included CC chemokines MCP-1 and TARC, CXC chemokines KC and MIP-2α, chemokine receptors Ccr1 and Cx3cr1 and related genes like matrix metalloproteinases. Microarray data of 1 and 7 days were confirmed for 17 up-regulated genes by QRT–PCR. (Immuno)histochemical analysis showed that the inflammatory and repair phase after renal I/R injury take place after, respectively, 1 and 7 days. Interestingly, chemokine expression was highest during the repair phase. In addition, expression profiles showed a biphasic expression of all up-regulated CXC chemokines coinciding with the early inflammatory and late repair phase. In conclusion, we propose that temporal expression of chemokines is a crucial factor in the regulation of renal I/R injury and repair

Medico-legal assessment of personal damage in older people: report from a multidisciplinary consensus conference

Ageing of the global population represents a challenge for national healthcare systems and healthcare professionals, including medico-legal experts, who assess personal damage in an increasing number of older people. Personal damage evaluation in older people is complex, and the scarcity of evidence is hindering the development of formal guidelines on the subject. The main objectives of the first multidisciplinary Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People were to increase knowledge on the subject and establish standard procedures in this field. The conference, organized according to the guidelines issued by the Italian National Institute of Health (ISS), was held in Bologna (Italy) on June 8, 2019 with the support of national scientific societies, professional organizations, and stakeholders. The Scientific Technical Committee prepared 16 questions on 4 thematic areas: (1) differences in injury outcomes in older people compared to younger people and their relevance in personal damage assessment; (2) pre-existing status reconstruction and evaluation; (3) medico-legal examination procedures; (4) multidimensional assessment and scales. The Scientific Secretariat reviewed relevant literature and documents, rated their quality, and summarized evidence. During conference plenary public sessions, 4 pairs of experts reported on each thematic area. After the last session, a multidisciplinary Jury Panel (15 members) drafted the consensus statements. The present report describes Conference methods and results, including a summary of evidence supporting each statement, and areas requiring further investigation. The methodological recommendations issued during the Conference may be useful in several contexts of damage assessment, or to other medico-legal evaluation fields

GW501516, a PPARδ Agonist, Ameliorates Tubulointerstitial Inflammation in Proteinuric Kidney Disease via Inhibition of TAK1-NFκB Pathway in Mice

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(−). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases

A Molecular Signature of Proteinuria in Glomerulonephritis

Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 “albumin-regulated genes” differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n = 25) could be distinguished from those of control subjects (n = 6) based solely upon the expression of these 231 “albumin-regulated genes.” The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that all forms of primary glomerulonephritis (n = 33) can be distinguished from controls (n = 21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis